1. Field of the Invention
The invention relates to methods and kits for treating lymphoproliferative diseases comprising (co)administering to the host pentostatin, at least one alkylating agent and at least one methylated xanthine.
2. Description of Related Art
In spite of the chemosensitivity seen with the initial treatment of malignant lymphoproliferative diseases, relapse is uniform and death commonly occurs as a result of disease progression. One example of this is Chronic Lymphocytic Leukemia (CLL). CLL is the most common adult leukemia occurring in the western hemisphere and accounts for 25% of all leukemias. The extremely indolent natural history of both smoldering and early stage CLL has left many with the perception that this is a "good leukemia" that can be ignored until the advanced stage at which time palliative therapy is acceptable. K. R. Rai et al., Clinical Staging of Chronic Lymphocytic Leukemia, Blood 46:219-234 (1975); J. L. Binet et al., A New Prognostic Classification of Chronic Lymphocytic Leukemia Derived from a Multivariate Survival Analysis, Cancer 48:198-216 (1981). This document, and all others cited to herein, are incorporated by reference as if reproduced fully herein.
A contrary interpretation of the available data on CLL is that it is currently an incurable illness with advanced stage patients having a median survival of 18 months to 3 years. J. S. Lee et al., Prognosis of Chronic Lymphocytic Leukemia: A Multivariate Regression Analysis of 325 Untreated Patients, Blood 69:929-936 (1987); E. Montserratt et al., Chronic Lymphocytic Leukemia: Prognostic Factors and Natural History, Baillieres Clin Haematol 6:849-866 (1993). For the patient younger than 50 years, even the diagnosis of early stage CLL shortens expected survival by an average of 19 years. E. Montserrat et al., Presenting Features and Prognosis of Chronic Lymphocytic Leukemia in Younger Adults, Blood 78:1545-1551 (1991).
Disease frequency and expected death rate derived from the Surveillance, Epidemiology, and End Results program further discredit the former paradigm. S. L. Parker et al., Cancer Statistics, 1997, CA Cancer J Clin 47:5-27 (1997). Approximately 7,400 patients may have been diagnosed with CLL in the United States during 1997, with 4,300 dying during that same period as a direct result of this disease. This absolute death rate is several times that observed in all combined pediatric tumors and similar or slightly lower than that observed in many adult solid tumors.
The reasons for the incurability of lymphoproliferative diseases may stem from intrinsic biologic drug resistance related to many factors, including inactivation of the p53 tumor suppressor gene and overexpression of the apoptotic protein bcl-2.
Bcl-2 overexpression and aberrant p53 function are frequently observed in low-grade B-cell and T-Cell lymphomas. Tumor overexpression of bcl-2 protein may be associated with marked resistance to apoptosis induced by chemotherapy or radiation and has been associated with a worse outcome. T. Miyashita et al., Bcl-2 Oncoprotein Blocks Chemotherapy-induced Apoptosis in a Human Leukemia Cell Fine, Blood 81:151-157 (1993); L. Sachs et Al., Control of Programmed Cell Death in Normal and Leukemic Cells: New Implications for Therapy, Blood 82:15-21 (1993); O. Hermine et al., Prognositic Significance of Bcl-2 Expression in Aggressive Non-hodgkin's Lymphoma, Blood 87: 265-272 (1996). Aberrant p53 function is also associated with both a poor treatment response and inferior survival in these disorders. K. Dohner et al., p 53 Gene Deletion Predicts for Poor Survival and Non-response to Therapy with Purine Analogs in Chronic B-cell Leukemias, Blood 85:1580-1589 (1995); A. Ichikawa et al., Mutations of the P53 Gene as a Prognostic Factor in Aggressive B-cell Lymphoma, NEJM 337: 529-34 (1997); E. Wattel et al., p53 Mutation Are Associated with Resistance to Chemotherapy and Short Survival in Hematologic Malignancies, Blood 84: 3148-3157 (1994).
In the case of CLL in particular, the central decision of the physician caring for a CLL patient was when to initiate treatment and what schedule of alkylator therapy to use. Results from a large French Cooperative Group study comparing immediate versus delayed chlorambucil therapy in early (Binet A) stage patients showed an inferior survival rate for the patients who had an early therapeutic intervention. French Cooperative Group on Chronic Lymphocytic Leukemia, Effects of Chlorambucil and Therapeutic Decision in initial Forms of Chronic Lymphocytic Leukemia (Stage A), Blood 1414-1421 (1990). This unexpected poor outcome in the patients receiving immediate therapy was partially attributed to a higher frequency of epithelial malignancies.
Once therapeutic intervention has been deemed necessary, the task of deciding what therapy is appropriate for the individual patient is equally challenging. Conventionally, initial treatment of patients with symptomatic CLL has often involved therapy with chlorambucil with or without prednisone. The addition of prednisone is based on a small 26-patient comparative study of chlorambucil versus chlorambucil plus prednisone that noted an improved response rate but similar survival in patients receiving this combination. T. Han et al., Chlorambucil Versus Combined Chlorambucil-corticosteroid Therapy in Chronic Lymphocytic Leukemia, Cancer 31:502-508 (1973).
Corticosteroids as a single agent have minimal activity against CLL, predispose the patient to a higher risk of infections, and may aggravate hyperlymphocytosis. P. A. Kyle et al., Large Doses of Prednisone and Prednisolone in the Treatment of Malignant Proliferative Disorders, Ann Intern Med 57:717-731 (1962). Comparative trials of combination therapy to single-agent chlorambucil have shown similar or improved response, but no impact on survival. E. Montserrat et al., Treatment of Chronic Lymphocytic Leukemia in Advanced Stages, Cancer 56:2369-2375 (1985); The French Cooperative Group on Chronic Lymphocytic Leukemia, A Randomized Clinical Trial of Chlorambucil Versus COP in Stage B Chronic Lymphocytic Leukemia, Blood 75:1422 (1990) (abstr); B. Raphael et al., Comparison of Chlorambucil and Prednisone Versus Cyclophosphamide, Vincristine, and Prednisone as Initial Treatment for Chronic Lymphocytic Leukemia: Long Term Follow-up of the Eastern Cooperative Oncology Group Randomized Clinical Trial, J Clin Oncol 9:770-776 (1990).
In an attempt to improve CLL treatment, physicians have also turned to the purine analog fludarabine. Results from several large phase II studies led by the MD Anderson Leukemia group and others in previously treated and untreated CLL patients noted a 31% to 57%, and 78% response rate, respectively. M. R. Grever et al., Fludarabine Monophosphate: A Potentially Useful Agent in Chronic Lymphocytic Leukemia, Nouv Rev Fr Hematol 30:437-459 (1988); M. J. Keating, Fludarabine Phosphate in the Treatment of Chronic Lymphocytic Leukemia, Semin Oncol 17:49-62 (1990); M. J. Keating et al., Fludarabine: A New Agent with Marked Cytoreductive Activity in Untreated Chronic Lymphocytic Leukemia, J Clin Oncol 9:44-49 (1991).
Attempts to improve on the outcome of therapy in CLL and other hematologic malignancies has occurred through rational combination approaches with utilizing agents with non-overlapping toxicity. Pre-clinical data (Proc Am Ass Cancer Res 38: 2a, 1997, Biochem Pharmacol 44: 2220, 1992) suggest synergistic interaction between DNA damaging agents and the purine analogs or pentostatin. Based on these data, combination studies with alkylating agents and one of the purine analogs have been performed. (Leukemia 8: 1290, 1994; Leukemia 7: 361,1993; Blood 84s: 383a, 1994). With respect to fludarabine, these studies demonstrated that myelosupression was more problematic, and compromised the total administered dose of each agent. Three phase 11 designs were initiated with fludarabine and cyclophosphamide using either greatly attenuated doses of fludarabine and cyclophosphamide (Regimen A, Blood 88s: 480a, 1994), somewhat less attenuated doses of these therapies with filgrastim support (Regimen B, Blood 92s: 104a, 1998) and sequential therapy (cyclophosphamide single agent therapy followed by fludarabine monotherapy(Regimen C, Blood 88s: 481 a, 1996). A summary of response these studies in untreated patients is shown in Table 1 below.
Number of % Complete % Complete + Reg Agents Utilized Patients Remission Partial Remission A FLU + CY 14 (30)* 93 B FLU + CY + 20 50 100 G-CSF C FLU Then CY 18 33 89 Key: Ref--reference; FLU--fludarabine; CY--cyclophosphamide; *From presentation
Impressive tumor cytoreduction was noted in all series. However, the frequency of complete response rate as compared to that expected with fludarabine monotherapy was not appreciably increased with the attenuated dose or sequential therapy. In a separate study, Oken and colleagues combined the less myelosuppressive agent pentostatin with chlorambucil and prednisone in untreated CLL patients and noted an overall response rate of 87%, including a 44% complete response rate. (Proc Am Soc Clin Oncol 17: 6a, 1998) Unlike many of the combination series reported to date, long term follow-up was available demonstrating a median response duration that had not reached at greater than 32 months. Opportunistic infections were problematic in this study, likely as a consequence of the corticosteroids in the absence of antimicrobial and antiviral prophylaxis.
Accordingly, there still remains room for improvement in the treatment of chronic lymphocytic leukemia, and other lymphoproliferative diseases. Accordingly, there is a need for improvement in treating lymphoproliferative diseases.